The activation of B cells and their differentiation into antibody secreting cells is triggered by antigen and requires T helper (Th) cells. Not only do Th cells control activation of B cells, they also control isotype switching (IgM to IgG) and initiate somatic hypermutation. (Janeway et al., Immunobiology, Garland Publishing, New York, 1997). Th cells also play an important role in activating macrophages and in coordinating the response of the host to intracellular pathogens.
The proteins most responsible for controlling the interaction between Th cells and various target cells are CD40 and CD40 ligand (CD40L). Interaction of membrane-bound CD40 and CD40L triggers B-cell activation. Preventing formation of the CD40-CD40L complex (as with, e.g., monoclonal antibodies) has been shown to inhibit (i) murine AIDS-associated splenomegaly, hypergammaglobulinemia, and immunodeficiency in disease susceptible mice (Green et al. J. Virol. 70:2569, 1996); (ii) insulinitis and diabetes in nonobese diabetic mice (Balasa et al. J. Immunol. 159:4620, 1997); (iii) murine thyroiditis (Carayanniotis et al. Immunology 90:421, 1997); (iv) CD4+ T cell mediated alloreactivity after bone marrow transplantation (Blazar et al., J. Immunol. 158:29, 1997); (v) the immune response to infection with recombinant adenovirus (Kay et al., Proc. Natl. Acad. Sci. U.S.A. 94:4686, 1997); (vi) allograft rejection of transplanted skin or cardiac tissue (Larsen et al. Nature 381:434, 1996); (vii) murine membranous glomerulonephritis (Biancone et al. Kidney Intl. 48:458, 1995); and (viii) lupus-nephritis in a murine model of systemic lupus erythematosus (Early et al. J. Immunol. 157:3159, 1996). Thus, it is clear that the interaction CD40 and CD40L plays an important role in normal and pathological immune system function.
CD40L is expressed in T cells., activated B cells, a subpopulation of blood dendritic cells, smooth muscle cells, and vascular endothelial cells and, importantly, is present as a soluble form in the blood (Grammar et. al., J. Immunol. 154:4996, 1995; Blossom et. al., J. Immunol. 159:4580, 1997; Pinchuk et. al., J. Immunol. 157:4363, 1996; and, Mach et. al., Proc. Natl. Acad. Sci. U.S.A. 94: 1931, 1997). Furthermore, the present inventors have found that CD40L is expressed in malignant cells, including, for example B cell malignancies such as chronic lymphocytic leukemia (CLL). The expression of CD40L on endothelial cells and smooth muscle cells also suggests that this protein plays an important role in the induction of vascular damage, as is observed, for example, in athersclerosis or thrombosis (Mach et al., Proc. Natl. Acad. Sci. U.S.A. 94:1931, 1997). Because of the importance of CD40L in a wide range of diseases or disease processes, such as, e.g., inflammation, there is a need in the art for a reliable diagnostic and prognostic method to monitor disease activity and response to therapy, by assaying the expression or presence of CD40L.
CD40L is a 261-amino acid type II transmembrane protein. One or more biologically active soluble forms of the molecule, collectively designated sCD40L, are produced by proteolytic cleavage of the full-length form, which may occur intracellularly or on the cell surface. sCD40L is important in inflammation. For example, an sCD40L fusion protein (CD40L-CD8) induced a pulmonary inflammatory response in transgenic mice expressing the soluble protein. (Wiley et al. J. Immunol. 158:2932 (1997).
When a patient is diagnosed with an autoimmune disease such as sytemic lupus erythematosus (SLE), a B cell malignancy such as CLL, an inflammatory process, or a vascular disease such as atherosclerosis or thrombosis, the choice of appropriate therapeutic interventions would be considerably facilitated by diagnostic and prognostic indicators that accurately reflect the current severity of the disease, predict future severity, and monitor response to therapy. Thus, there is a need in the art for reliable diagnostic and prognostic methods to monitor disease activity and response to therapy in patients suffering from autoimmune disease.